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【结 构 式】 
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【分子编号】49278 【品名】(2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal 【CA登记号】 |
【 分 子 式 】C24H41NO3SSi 【 分 子 量 】451.74598 【元素组成】C 63.81% H 9.15% N 3.1% O 10.63% S 7.1% Si 6.22% |
合成路线1
该中间体在本合成路线中的序号：(XXIII)The reduction of the methyl ester of (XVI) with DIBAL in dichloromethane gives the aldehyde (XVIII), which is condensed with the chiral phosphonate (XIX) by means of BuLi in ethyl ether to yield the enoylsultam (XX). The methylation of (XX) with L-selectride and methyl iodide affords the methylated sultam (XXI), which is desilylated with TBAF and reprotected with Tes-Cl and TEA to provide triethylsilyl ether (XXII) with a more favorable silyl leaving group needed in the remaining synthetic steps. Elimination of the sultam group of (XXII) by means of DIBAL in dichloromethane gives the aldehyde (XXIII), which is condensed with the ketone (XXIV) by means of LDA to yield the aldol (XXV). The protection of the OH group of (XXV) with Troc-Cl ad pyridine affords compound (XXVI), which is oxidized at the terminal vinyl group by means of OsO4 and NaIO4 to provide the aldehyde (XXVII). The selective desilylation of (XXVII) by means of HF and pyridine furnishes the hydroxy aldehyde (XXVIII).
| 【1】 Martin, H.J.; et al.; How stable are epoxides? A novel synthesis of epothilone B. Angew Chem. Int Ed Engl 2000, 39, 3, 581. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 49271 | methyl 3-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]propanoate | C22H37NO4SSi | 详情 | 详情 | |
| (XVIII) | 49273 | 3-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]propanal | C21H35NO3SSi | 详情 | 详情 | |
| (XIX) | 49274 | diethyl 2-(10,10-dimethyl-2,2-dioxo-2lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl)-2-oxoethylphosphonate | C16H28NO6PS | 详情 | 详情 | |
| (XX) | 49275 | 4-((E)-5-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-2-pentenoyl)-10,10-dimethyl-2lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-2,2-dione | C33H52N2O5S2Si | 详情 | 详情 | |
| (XXI) | 49276 | 4-((2S)-5-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-2-methylpentanoyl)-10,10-dimethyl-2lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-2,2-dione | C34H56N2O5S2Si | 详情 | 详情 | |
| (XXII) | 49277 | 10,10-dimethyl-4-[(2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanoyl]-2lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-2,2-dione | C34H56N2O5S2Si | 详情 | 详情 | |
| (XXIII) | 49278 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal | C24H41NO3SSi | 详情 | 详情 | |
| (XXIV) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XXV) | 49279 | (4S,7R,8R,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-12-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-dodecen-6-one | C40H73NO5SSi2 | 详情 | 详情 | |
| (XXVI) | 49280 | (1R,2R,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4,4-trimethyl-1-[(1S)-1-methyl-4-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)butyl]-3-oxo-7-octenyl 2,2,2-trichloroethyl carbonate | C43H74Cl3NO7SSi2 | 详情 | 详情 | |
| (XXVII) | 49281 | (1R,2R,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4,4-trimethyl-1-[(1S)-1-methyl-4-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)butyl]-3,7-dioxoheptyl 2,2,2-trichloroethyl carbonate | C42H72Cl3NO8SSi2 | 详情 | 详情 | |
| (XXVIII) | 49282 | (1R,2R,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-1-((1S)-4-[(2R,3S)-3-[(2S,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-1-methylbutyl)-2,4,4-trimethyl-3,7-dioxoheptyl 2,2,2-trichloroethyl carbonate | C36H58Cl3NO8SSi | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)The cyclization of phosphonate (I) with the chiral alcohol (II) by means of tert-butyl hypochlorite and Et-MgBr gives the isoxazoline (III), which is condensed with 2-methylthiazole-4-carbaldehyde (IV) by means of DBU and LiCl in acetonitrile to yield the secondary alcohol (V). The oxidation of (V) with TPAP and NMO in dichloromethane affords the corresponding ketone (VI), which is treated with the Grignard reagent (VII) in THF to provide the expected secondary alcohol (VIII). The silylation of (VIII) with Tes-OTf in dichloromethane gives the silyl ether (IX), which is treated with SmI2, Et3B and NaBH4 to cleave the isoxazoline ring and yield the diol (X). The reaction of (X) with SOCl2, TEA and TBAF affords the chiral epoxide (XI), which is silylated with Tes-Cl and TEA to provide the silyl ether (XII). The selective hydrolysis of the primary silyl ether of (XII) with HOAc in THF/water gives the primary alcohol (XIII), which is oxidized with TPAP and NMO in dichloromethane to yield the corresponding aldehyde (XIV). The condensation of (XIV) with ketone (XV) by means of LDA affords the open-chain precursor (XVI).
| 【1】 Bode, J.W.; Carreira, E.M.; Stereoselective syntheses of epothilones A and B via directed nitrile oxide cycloaddition. J Am Chem Soc 2001, 123, 18, 3611. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 49286 | diethyl 2-(hydroxyimino)-1-methylethylphosphonate | C7H16NO4P | 详情 | 详情 | |
| (II) | 49287 | (2R)-3-buten-2-ol | 33447-72-2 | C4H8O | 详情 | 详情 |
| (III) | 49288 | diethyl 1-[(5R)-5-[(1R)-1-hydroxyethyl]-4,5-dihydro-3-isoxazolyl]ethylphosphonate | C11H22NO5P | 详情 | 详情 | |
| (IV) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (V) | 49289 | (1R)-1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-1-ethanol | C12H16N2O2S | 详情 | 详情 | |
| (VI) | 49290 | 1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-1-ethanone | C12H14N2O2S | 详情 | 详情 | |
| (VII) | 49291 | bromo[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]magnesium | C15H33BrMgOSi | 详情 | 详情 | |
| (VIII) | 49292 | (2R,6S)-6-methyl-2-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-7-[(triisopropylsilyl)oxy]-2-heptanol | C27H48N2O3SSi | 详情 | 详情 | |
| (IX) | 49293 | (5R)-5-[(1R,5S)-1,5-dimethyl-1-[(triethylsilyl)oxy]-6-[(triisopropylsilyl)oxy]hexyl]-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydroisoxazole; (1R,5S)-1,5-dimethyl-1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-6-[(triisopropylsilyl)oxy]hexyl triethylsilyl ether | C33H62N2O3SSi2 | 详情 | 详情 | |
| (X) | 49294 | (E,3S,5R,6R,10S)-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-6-[(triethylsilyl)oxy]-11-[(triisopropylsilyl)oxy]-1-undecene-3,5-diol | C33H65NO4SSi2 | 详情 | 详情 | |
| (XI) | 49295 | (2S,3E)-3-methyl-1-((2S,3R)-3-methyl-3-[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]oxiranyl)-4-(2-methyl-1,3-thiazol-4-yl)-3-buten-2-ol | C27H49NO3SSi | 详情 | 详情 | |
| (XII) | 49296 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentyl triisopropylsilyl ether; 2-methyl-4-[(E,3S)-2-methyl-4-((2S,3R)-3-methyl-3-[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]oxiranyl)-3-[(triethylsilyl)oxy]-1-butenyl]-1,3-thiazole | C33H63NO3SSi2 | 详情 | 详情 | |
| (XIII) | 49297 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-pentanol | C24H43NO3SSi | 详情 | 详情 | |
| (XIV) | 49278 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal | C24H41NO3SSi | 详情 | 详情 | |
| (XV) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XVI) | 49298 | (4S,7R,8S,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-12-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-dodecen-6-one | C40H73NO5SSi2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XV)The reaction of the oxime (I) with the 1-methylallyl alcohol (II) by means of Et-MgBr gives the isoxazoline (III), which is condensed with 2-methylthiazole-4-carbaldehyde (IV) by means of DBU and LiCl in acetonitrile to yield the adduct (V). The oxidation of (V) with TPAP and NMO affords the methyl ketone (VI), which is condensed with the Grignard reagent (VII) in THF to provide the tertiary alcohol (VIII). The protection of (VIII) by means of Tes-OTf gives the silylated compound (IX), which is oxidated with SmI2 in THF to yield the beta-hydroxy ketone (X). The reduction of (X) with Et3B and NaBH4 in THF/methanol affords the beta-diol (XI), which is treated with SOCl2, TEA and TBAF to provide the epoxide derivative (XII). The silylation of both OH groups of (XII) by means of Tes-Cl and TEA in dichloromethane furnishes the bis-silyl ether (XIII), which is selectively monodesilylated by means of AcOH in THF/water to give the primary alcohol (XIV). The oxidation of this alcohol by means of TPAP and NMO yields the carbaldehyde (XV).
| 【1】 Bode, J.W.; Carreira, E.M.; Stereoselective syntheses of epothilones A and B via nitrile oxide cycloadditions and related studies. J Org Chem 2001, 66, 19, 6410. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 60651 | dipropyl (1S)-2-chloro-2-(hydroxyimino)-1-methylethylphosphonate | C9H19ClNO4P | 详情 | 详情 | |
| (II) | 49287 | (2R)-3-buten-2-ol | 33447-72-2 | C4H8O | 详情 | 详情 |
| (III) | 60652 | diethyl (1S)-1-{(5R)-5-[(1R)-1-hydroxyethyl]-4,5-dihydro-3-isoxazolyl}ethylphosphonate | C11H22NO5P | 详情 | 详情 | |
| (IV) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (V) | 49289 | (1R)-1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-1-ethanol | C12H16N2O2S | 详情 | 详情 | |
| (VI) | 49290 | 1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-1-ethanone | C12H14N2O2S | 详情 | 详情 | |
| (VII) | 49291 | bromo[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]magnesium | C15H33BrMgOSi | 详情 | 详情 | |
| (VIII) | 49292 | (2R,6S)-6-methyl-2-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-7-[(triisopropylsilyl)oxy]-2-heptanol | C27H48N2O3SSi | 详情 | 详情 | |
| (IX) | 49293 | (5R)-5-[(1R,5S)-1,5-dimethyl-1-[(triethylsilyl)oxy]-6-[(triisopropylsilyl)oxy]hexyl]-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydroisoxazole; (1R,5S)-1,5-dimethyl-1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-6-[(triisopropylsilyl)oxy]hexyl triethylsilyl ether | C33H62N2O3SSi2 | 详情 | 详情 | |
| (X) | 60653 | (E,5R,6R,10S)-5-hydroxy-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-6-[(triethylsilyl)oxy]-11-[(triisopropylsilyl)oxy]-1-undecen-3-one | C33H63NO4SSi2 | 详情 | 详情 | |
| (XI) | 49294 | (E,3S,5R,6R,10S)-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-6-[(triethylsilyl)oxy]-11-[(triisopropylsilyl)oxy]-1-undecene-3,5-diol | C33H65NO4SSi2 | 详情 | 详情 | |
| (XII) | 60654 | (2S,3E)-1-{(2S,3R)-3-[(4S)-5-hydroxy-4-methylpentyl]-3-methyloxiranyl}-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-buten-2-ol | C18H29NO3S | 详情 | 详情 | |
| (XIII) | 60655 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-{(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl}oxiranyl)pentyl triethylsilyl ether; 2-methyl-4-{(E,3S)-2-methyl-4-((2S,3R)-3-methyl-3-{(4S)-4-methyl-5-[(triethylsilyl)oxy]pentyl}oxiranyl)-3-[(triethylsilyl)oxy]-1-butenyl}-1,3-thiazole | C30H57NO3SSi2 | 详情 | 详情 | |
| (XIV) | 49297 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-pentanol | C24H43NO3SSi | 详情 | 详情 | |
| (XV) | 49278 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal | C24H41NO3SSi | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XV)The condensation of (XV) with the chiral ketone (XVI) by means of LDA in TH gives the aldol (XVII). The protection of the OH group of (XVII) with Troc-Cl and pyridine yields compound (XVIII), which is oxidized at the vinyl group by means of OsO4, NaIO4, selectively monodesilylated with HF and pyridine, and further oxidated with NaClO2 to afford the hydroxyacid (XIX). The Yamaguchi macrolactonization of (XIX) by means of 2,4,6-trichlorobenzoyl chloride provides the macrocyclic lactone (XX). Elimination of the Troc protecting group of (XX) by means of Zn and NH4Cl gives the silylated precursor (XXI), which is finally deprotected by means of HF and pyridine to yield the target epothilone B.
| 【1】 Bode, J.W.; Carreira, E.M.; Stereoselective syntheses of epothilones A and B via nitrile oxide cycloadditions and related studies. J Org Chem 2001, 66, 19, 6410. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 49278 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal | C24H41NO3SSi | 详情 | 详情 | |
| (XVI) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XVII) | 49298 | (4S,7R,8S,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-12-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-dodecen-6-one | C40H73NO5SSi2 | 详情 | 详情 | |
| (XVIII) | 60656 | trityl (3S,4R,7S)-7-{[tert-butyl(dimethyl)silyl]oxy}-4,6,6-trimethyl-3-[(1S)-1-methyl-4-((2R,3S)-2-methyl-3-{(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl}oxiranyl)butyl]-5-oxo-9-decenoate | C61H89NO6SSi2 | 详情 | 详情 | |
| (XIX) | 60657 | (3S,6R,7S,8S)-3-{[tert-butyl(dimethyl)silyl]oxy}-11-{(2R,3S)-3-[(2S,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl}-4,4,6,8-tetramethyl-5-oxo-7-[2-oxo-2-(trityloxy)ethyl]undecanoic acid | C54H73NO8SSi | 详情 | 详情 | |
| (XX) | 60658 | trityl 2-{(1S,3S,7S,10R,11S,12S,16R)-7-{[tert-butyl(dimethyl)silyl]oxy}-8,8,10,12,16-pentamethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-11-yl}acetate | C54H71NO7SSi | 详情 | 详情 | |
| (XXI) | 49303 | (1S,3S,7S,10R,11S,12S,16R)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-8,8,10,12,16-pentamethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione | C33H55NO6SSi | 详情 | 详情 |